FDA Approves Pembrolizumab Plus Chemotherapy for PD-L1+ Locally Recurrent Unresectable or Metastatic TNBC

The FDA has granted approval to pembrolizumab (Keytruda) in combination with chemotherapy as treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1, defined as having a combined positive score ([CPS] ≥10) as determined by an FDA-approved test.¹

As a companion diagnostic to aid in identifying patients with locally recurrent unresectable or metastatic TNBC who are likely to derive benefit from pembrolizumab plus chemotherapy, the PD-L1 IHC 22C3 pharmDx was also granted approval by the FDA.

Findings from the phase 3 KEYNOTE-355 clinical trial (NCT02819518) support the FDA approval of the combination. Achievement of the primary end point, progression-free survival (PFS) in KEYNOTE-355 was first announced in February 2020,² then the full study results were presented in a 2020 American Society of Clinical Oncology (ASCO) Virtual Annual Meeting,³ showing statistically significant and clinically meaningful improvement in PFS versus chemotherapy alone.

The study included 847 patients who were randomized 2:1 to receive either an intravenous (IV) 200-mg dose of pembrolizumab every 3 weeks in combination with chemotherapy or chemotherapy alone. The combination arm included 556 patients and the monotherapy arm had 281 patients. The chemotherapy drugs used in the study included nab-paclitaxel (Abraxane) by IV infusion at a dose of 100 mg/m2 on days 1, 8, and 15 every 4 weeks; IV paclitaxel at the 90-mg/m2 dose level on days 1, 8, and 15 every 4 weeks; or gemcitabine 1000 mg/m2 and carboplatin area under the curve (AUC) 2 on days 1 and 8 every 3 weeks. Further division of the study population included groups of patients with PD-L1 expression of CPS ≥10, CPS ≥1, as well as the intention-to-treat (ITT) population.

Results showed the median PFS was 9.7 months in the pembrolizumab plus chemotherapy arm compared with 5.6 months in the chemotherapy-alone arm (HR, 0.65; 95% CI, 0.49-0.86; one-sided P = .0012) in the CPS ≥10 population.

In the cohort of patients with CPS ≥1, the median PFS was 7.6 months in the pembrolizumab-plus-chemotherapy arm versus 5.6 months in the chemotherapy arm (HR, 0.74; 95% CI, 0.61-0.90; one-sided P = .0014). Notably, however, the PFS results did not meet the prespecified criteria for statistical significance.

The ITT population had a median PFS of 7.5 months with the pembrolizumab combination compared with 5.6 months with chemotherapy alone (HR, 0.82; 95% CI, 0.69-0.97).

These data showed that pembrolizumab plus chemotherapy was a favorable treatment in patients with locally recurrent unresectable or metastatic TNBC regardless of PD-L1 expression level. Patients who had a CPS <1 or CPS <10 were exceptions in this case. Overall survival analyses were not yet mature.

The safety of this combination was determined by the incidence of adverse events. The most common (≥20%) adverse events with pembrolizumab plus chemotherapy included fatigue, nausea, diarrhea, constipation, vomiting, alopecia, rash, cough, decreased appetite, and headache. Frequent (≥20%) laboratory abnormalities were anemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia, elevated alanine aminotransferase and aspartate aminotransferase, hyperglycemia, hypoalbuminemia, increased alkaline phosphatase, hypocalcemia, hyponatremia, hypophosphatemia, and hypokalemia.

Based on the safety findings of pembrolizumab plus chemotherapy, the FDA recommended that pembrolizumab be administered at 200 mg every 3 weeks or 400 mg every 6 weeks and be given prior to chemotherapy. The combination can be administered until disease progression, unacceptable toxicity, or for up to 24 months. The FDA also recommended specific dosing of paclitaxel, gemcitabine, and carboplatin when administered in combination with pembrolizumab. Specifically, paclitaxel should be given at 100 mg/m2 on days 1, 8 and 15 every 28 days, or paclitaxel 90 mg/m2 on days 1, 8 and 15 every 28 days, or gemcitabine 1000 mg/m2 plus carboplatin AUC 2 mg/mL/min on days 1 and 8 every 21 days is administered by IV infusion.

_Reference:

_{1. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. News release. FDA. November 13, 2020. Accessed November 13, 2020. https://bit.ly/32HVbTo​}

_{2. Merck’s Keytruda (pembrolizumab) in combination with chemotherapy met primary endpoint of progression-free survival (PFS) as first-line treatment for metastatic triple-negative breast cancer (mTNBC). News release. Merck. February 12, 2020. Accessed November 13, 2020. https://bit.ly/3lI7XZz}